Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019158 (hepatitis)
 30,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor necrosis factor (TNF) plays a key role in several types of fulminant and acute hepatitis, and induces massive apoptosis and necrosis of hepatocytes. Our previous studies described the central role played by several matrix metalloproteinases (MMPs) and one or more unknown serine proteases. The aim of this study was to investigate the involvement of serine proteases of the fibrinolytic pathway, known to be activators of several MMPs, in TNF-induced hepatitis and fibrinogen (FG) breakdown. Experiments were performed in a model of TNF-induced hepatitis, consisting of administration of TNF in combination with D-(+)-galactosamine (GalN) to mice deficient in urokinase-type plasminogen (PG) activator (u-PA), tissue-type PG activator (t-PA) or PG. Lethality, transaminase release, increased plasma clotting time and FG levels were measured. In PA- and PG-deficient mice, TNF/GalN still induced hepatitis, as well as increased clotting time and FG breakdown. MMP-9 activation still occurred in the liver despite the lack of plasmin. The data suggest that the serine proteases involved in TNF-induced lethal hepatitis are no constituents of the fibrinolytic cascade.
Cytokine 2003 Mar 21
PMID:Serine proteases of the fibrinolysis pathway are not involved in lethal hepatitis and fibrinogen breakdown induced by tumor necrosis factor. 1282 1

We compared the biological mechanism of cell death during hepatotoxicity induced by ligation of the Fas receptor in wild-type and liver-specific bcl-2 transgenic mice. Transgenic overexpression of Bcl-2 in mouse hepatocytes can prevent lethal hepatitis induced by agonistic anti-Fas antibodies. In contrast, Fas ligand (FasL)-induced death cannot be overcome in bcl-2 transgenic mice, indicating that anti-Fas antibodies do not reliably mimic the more physiological ligand. Different apoptotic parameters, viz. caspase activation, cytochrome c release and nuclear DNA degradation were analysed. No differences, however, could be observed between wild-type and bcl-2 transgenic mice after injection with a lethal dose of soluble FasL, indicating that apoptosis by FasL-dependent ligation is not modulated by Bcl-2 in vivo. These results demonstrate that the stimulus determines the outcome between type I mitochondria-independent apoptosis, in the case of FasL, or type II mitochondria-dependent and Bcl-2-inhibitable apoptosis, in the case of anti-Fas antibodies.
Cytokine 2003 May
PMID:A Bcl-2 transgene expressed in hepatocytes does not protect mice from fulminant liver destruction induced by Fas ligand. 1284 4

Bidens pilosa is an annual plant from tropical America with anti-inflammatory properties in hepatitis, laryngitis, headache and digestive disorders, among others. Its wide pharmacological applications can be attributed to its chemical composition, with inhibitory effects on pathogenic microorganisms and flavonoids, which show strong antioxidant capacities. We investigated the antioxidant activity of an aqueous infusion of Bidens pilosa by studying its protective effect on the hemolysis induced by an initiator of radicals such as 2,2'-azobis(2-amidinopropane) dihydrochloride (AAPH). The immunomodulatory activity of the infusion was tested using whole blood cells. Cytokine production increased in whole blood stimulated or not by lipopolysaccharides (LPSs). The infusion is also characterized by its capacity to protect erythrocytes from the phototoxic effect of chlorpromazine, which allows its use as a potential photoprotector. Finally, it did not show ocular irritation, as demonstrated by the effect on hemoglobin denaturation. This study supports the health benefits of the ingestion of the infusion.
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PMID:In vitro study of the antioxidant and immunomodulatory activity of aqueous infusion of Bidens pilosa. 1523 71

Immunotherapy with interferon-alpha (IFN-alpha) induces neuropsychiatric side effects, most notably depression. In hepatitis patients treated with IFN-alpha, severity of depression correlates with a decrease in serum activity of dipeptidyl peptidase IV (DPP-IV, EC 3.4.14.5), a membrane-bound protease involved in the cleavage of cytokines and neuroactive peptides. Abnormal serum activity of the cytosolic peptidase prolyl endopeptidase (PEP, EC 3.4.21.26, postprolyl cleaving enzyme, prolyl oligopeptidase) has been documented in patients with a variety of psychiatric disorders, most consistently in mood disorders. The serum activity of PEP and DPP-IV was measured before and after 4 weeks of high-dose induction treatment with IFN-alpha in 18 patients with high-risk melanoma. In this exploratory study, we show a clear decrease in the serum activity of PEP after 4 weeks of treatment with IFN-alpha. This decrease was not related to changes in hematologic parameters. In contrast, serum activity of DPP-IV did not change. Further studies focusing on a possible role of PEP in the pathophysiology of IFN-alpha-induced depression are warranted.
J Interferon Cytokine Res 2004 Jul
PMID:Serum activity of prolyl endopeptidase, but not of dipeptidyl peptidase IV, is decreased by immunotherapy with IFN-alpha in high-risk melanoma patients. 1529 52

Dehydroepiandrosterone (DHEA), one of the major androgens secreted by the adrenal cortex, has been shown to have potential immunoreguratory properties. In this study, we examined the effect of DHEA in a mouse model of hepatitis. Mice were treated with DHEA and injected with concanavalin A (Con A) or lipopolysaccharide (LPS)/D-galactosamine (GalN). Cytokine expression was measured by quantitative RT-PCR and ELISA. Apoptosis was detected by the TUNEL method and by DNA fragmentation analysis. In the DHEA-treated mice, the serum levels of ALT and expression of inflammatory mediators were significantly decreased. The number of apoptotic cells was also much lower than that observed in control, untreated mouse liver tissue. There were fewer tumor necrosis factor-alpha (TNF-alpha)-induced apoptotic cells in H4IIE hepatoma cells treated with DHEA than in non-treated cells. DHEA decreased the expression levels of mRNA transcripts encoding TNF-alpha and iNOS. These results suggest that DHEA can reduce T-cell-mediated injury in the liver as manifest by inhibition of the expression of several inflammatory mediators and hepatocyte apoptosis. DHEA should, thus, be considered as a novel candidate for the therapy of liver injury.
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PMID:A novel therapy for acute hepatitis utilizing dehydroepiandrosterone in the murine model of hepatitis. 1549 18

HBV and HCV infections are associated with the increased production of reactive oxygen species (ROS) within the liver that are responsible for the oxidation of intracellular molecules and activation transcription factors. The aim of the present study was to establish whether the presence of hepatitis could be implicated in the elevation of oxidative stress (SOX) and plasma proinflammatory and chemoattractant cytokine levels in uraemic patients. The markers of SOX-autoantibodies to oxidized LDL (OxLDL-Ab); total peroxides; and the major antioxidant enzyme Cu/Zn superoxide dismutase (Cu/Zn SOD); as well as tumor necrosis factor-alpha (TNF-alpha); regulated upon activation, normal T cell expressed and secreted (RANTES); and macrophage inflammatory protein-1alpha (MIP-1alpha) and beta (MIP-1beta) levels were measured in the plasma of uraemic patients with hepatitis in comparison to subjects without hepatitis and to healthy volunteers. The values of total peroxide, Cu/Zn SOD, TNF-alpha, and MIP-1beta, were significantly elevated in uraemic patients when compared to the controls, whereas RANTES were decreased. MIP-1alpha and OxLDL-Ab were similar in the two groups. Cu/Zn SOD, MIP-1beta and RANTES concentrations were significantly higher in the hepatitis-positive relative to the hepatitis-negative group. Both MIP-1beta and RANTES were directly associated with Cu/Zn SOD levels and the presence of hepatitis. Multiple stepwise regression analysis has shown that the duration of dialysis, followed by the presence of hepatitis, independently and significantly predicted increased Cu/Zn SOD levels, whereas elevated Cu/Zn SOD as an independent variable was significantly associated with both increased both MIP-1beta and RANTES in uraemic patients. These results suggest that the presence of viral hepatitis status and liver injury are novel determinants of increased oxidative stress, as well as of increased MIP-1beta and RANTES levels in uraemic patients.
Cytokine 2004 Dec 21
PMID:Hepatitis intensified oxidative stress, MIP-1beta and RANTES plasma levels in uraemic patients. 1556 48

NKT cells expressing phenotypic markers of both T and NK cells seem to be pivotal in murine models of immune-mediated liver injury, e.g., in Con A-induced hepatitis. Also alpha-galactosylceramide (alpha-GalCer), a specific ligand for invariant Valpha14 NKT cells, induces hepatic injury. To improve the comprehension of NKT-cell mediated liver injury, we investigated concomitants and prerequisites of alpha-GalCer-induced hepatitis in mice. Liver injury induced by alpha-GalCer injection into C57BL/6 mice was accompanied by intrahepatic caspase-3 activity but appeared independent thereof. alpha-GalCer injection also induces pronounced cytokine responses, including TNF-alpha, IFN-gamma, IL-2, IL-4, and IL-6. We provide a detailed time course for the expression of these cytokines, both in liver and plasma. Cytokine neutralization revealed that, unlike Con A-induced hepatitis, IFN-gamma is not only dispensable for alpha-GalCer-induced hepatotoxicity but even appears to exert protective effects. In contrast, TNF-alpha was clearly identified as an important mediator for hepatic injury in this model that increased Fas ligand expression on NKT cells. Whereas intrahepatic Kupffer cells are known as a pivotal source for TNF-alpha in Con A-induced hepatitis, they were nonessential for alpha-GalCer-mediated hepatotoxicity. In alpha-GalCer-treated mice, TNF-alpha was produced by intrahepatic lymphocytes, in particular NKT cells. BALB/c mice were significantly less susceptible to alpha-GalCer-induced liver injury than C57BL/6 mice, in particular upon pretreatment with d-galactosamine, a hepatocyte-specific sensitizer to TNF-alpha-mediated injury. Finally, we demonstrate resemblance of murine alpha-GalCer-induced hepatitis to human autoimmune-like liver disorders. The particular features of this model compared with other immune-mediated hepatitis models may enhance comprehension of basic mechanisms in the etiopathogenesis of NKT cell-comprising liver disorders.
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PMID:Alpha-galactosylceramide-induced liver injury in mice is mediated by TNF-alpha but independent of Kupffer cells. 1603 92

The woodchuck together with the woodchuck hepatitis virus (WHV) is an excellent model to study the pathogenesis of hepadnaviral infections. Chronic WHV infection causes severe liver disease and hepatocellular carcinoma in woodchucks. The mechanism of viral clearance is not fully understood, interferons seem to play a major role in down-regulating viral replication prior to elimination of infected hepatocytes. We investigated on the pattern of cytokine and T-cell-marker expression in livers of woodchucks chronically infected with WHV. RNase-protection-assay (RPA) was used to determine mRNA of woodchuck specific genes (TNF-alpha, IFN-gamma, IL-15, CD3, CD4, CD8). Serial liver biopsies were performed daily or weekly in eight chronic WHV-carrier woodchucks. Cytokine/T-cell-marker expression differed significantly between the time points up to +/-50% within each woodchuck. The different expression patterns of cytokines or T-cell-markers did not correlate to the (weak) fluctuations in the viremia but may explain the observed fluctuations in the WHV/HBV-load in chronically infected individuals. Furthermore, we observed associations between cytokine and T-cell-marker expression. The marginal fluctuations in viremia during the chronic infection may indicate, that, once the chronic hepadnaviral infection is established, cytokines/interferons expressed endogenously (i.e. not vector-borne or injected) play only a minor role.
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PMID:Fluctuation of the cytokine expression in the liver during the chronic woodchuck hepatitis virus (WHV) infection is not related to viral load. 1604 39

N-[1-(4-[4-(pyrimidin-2-yl)piperazin-1-yl]methyl phenyl)cyclopropyl] acetamide . HCl (Y-40138) suppresses liver injury in concanavalin A- and D-galactosamine/lipopolysaccharide (LPS)-induced mouse hepatitis models. However, the mechanism of action of Y-40138 has not been fully investigated. In this study, we examined the effect of Y-40138 on cytokine production in mice. Cytokine production was induced by intraperitoneal injection of LPS (0.5 mg kg(-1)) or intravenous injection of recombinant mouse tumour necrosis factor (TNF)-alpha (10 mug mouse(-1)) in BALB/c mice. TNF-alpha and interleukin (IL)-10 reached maximum levels 1.5 h after the LPS injection. IL-12 and interferon-sigma (IFN-sigma) reached maximum levels 3 to 9 h after the injection. When Y-40138 was orally administered 30 min prior to the injection, it inhibited TNF-alpha, IL-12 and IFN-sigma production and augmented IL-10 production. Y-40138 also inhibited IL-12 production and augmented IL-10 production in TNF-alpha-stimulated mice. In IL-10 knockout mice, Y-40138 inhibited TNF-alpha and IL-12 production 1.5 h after the LPS injection but not after 3 h or later, unlike in wild mice. In addition, TNF-alpha production was inhibited by Y-40138 at concentrations that could not augment IL-10 production. These data suggest that Y-40138 modulates pro-inflammatory cytokine production by both IL-10-dependent and -independent mechanisms.
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PMID:Treatment with Y-40138, a multiple cytokine production modulator, inhibits lipopolysaccharide- or tumour necrosis factor-alpha-induced production of pro-inflammatory cytokines and augments interleukin-10. 1625 79

Interleukin 15 (IL-15) is a member of the four-helix bundle cytokine family and has T cell growth factor activity. IL-15 plays a unique role in both innate and adaptive immune cell homeostasis, particularly for the development of NK cells and CD8+memory cells. It may be useful for stimulation of specific immune responses in chronic viral infection such as hepatitis B virus infection. The woodchuck model is an informative animal model for studies on hepadnavirus infection and therapeutic interventions. Here, the complete coding sequence of woodchuck IL-15 (wIL-15) was cloned and sequenced. wIL-15 shows a high homology (>70%) to its counterparts of other mammalian species. His-tagged recombinant wIL-15 protein was expressed and purified and showed the ability to promote the proliferation of activated mouse splenocytes and woodchuck peripheral blood lymphocytes. Further, examination of mRNA amounts in liver samples of woodchucks by semi-quantitative RT-PCR showed a slightly increased expression of wIL-15 in woodchuck livers during chronic woodchuck hepatitis virus infection. This available information will provide a basis for further studies on the function of IL-15 in the context of acute and chronic hepadnavirus infection and its potential therapeutic use for chronic hepatitis B virus infection in the woodchuck model.
Cytokine 2005 Dec 21
PMID:Molecular characterization of woodchuck interleukin 15 (wIL-15) and detection of its expression in liver samples of woodchucks infected with woodchuck hepatitis virus (WHV). 1640 57


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